The development of total parenteral nutrition (TPN) represents one of the major technological advances in medicine of the past two decades. However, rigorous scientific investigations into underlying physiologic principles has in many respects failed to keep pace with the rapidly advancing technology. In broad terms these studies seek to strengthen the scientific underpinnings of this rapidly growing field, in an effort to help guide the rational deployment of this valuable (and expensive) technology. Specifically, these studies examine the mechanisms underlying the influence of parenteral caloric substrates on protein metabolism in man. One series of studies investigates the comparative effects of different caloric substrates infused together with amino acids. These studies are designed to simulate the situation of clinical TPN. State-of-the-art techniques for in vivo assessment of protein metabolism will be employed, including a unique combination of the organ balance technique with the measurement of leucine kinetics (using L-(1-14C) leucine). While abundant previous data indicate similar nitrogern retention with different caloric substrates, the question of how the underlying physiologic mechanisms may differ (e.g., sites of amino acid deposition, rates of protein synthesis and breakdown) has never been systematically studied. The second series of studies critically examines the role of insulin in the unique protein-sparing effect of carbohydrate during fasting. Although this effect has been recognized for decades, the precise contribution of insulin has never been established. These studies utilize somatostatin and different carbohydrates to compare protein-sparing under conditions of varying stimulation of endogenous insulin secretion.